Table 1.
Major clinical studies of PT and HCC.
| Author, date | Center | Observation Period | Type of Study | Patient/Study CharacteristiCs | N° Patients | Median age | Performance status | Liver function (Child-Pugh) | Proton technique | Treatment Regimen Range | Equivalent dose 2 Gy/fr a/b = 10 | tumor size(range) | median FUP (range) | LC | os | Toxicity≥g3 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Su et al , 2022 | Chang Gung Memorial Hospital, Taiwan | 2016-2019 | retrospective | PT combined with anti-PD1/PDL1 | 29 | 60 | PS 0 16 pts, PS 1 13 pts | CP A5 23 pts, CP A6 6 pts | PSC | 66 Gy/10 fr 3 pts 72.6 Gy /22 fr 18 pts 60 Gy/ 10 fr 2 pts 50 Gy/10 fr 2 pts 45 Gy/10 fr 1 pt 33 Gy/5 fr 2 pts 33 Gy/10 fr 1 pt |
109.6 Gy10
96.6 Gy10 96 Gy10 75 Gy10 65.3 Gy10 54.8 Gy10 43.9 Gy10 |
≥ 5cm 19 pts | 13 mo (1/48.1) | 80% at 1 yr | 63% at 2 yr | 1 G3 dermatitis 1 G3 thrombocytopenia 3 G3 liver enzyme increase 4 G3 GI bleeding 1 G4 bilirubine increase 1 G4 biliary stricture 2 G5 hepatic failure 1 G5 duodenal perforation |
| Lee et al, 2022 | Chang Gung Memorial Hospital, Taiwan | 11/2015-02/2021 | retrospective | unresectable HCC with bile duct invasion | 20 | 61.5 | PS 0 7 pts, PS 1 23 pts | CP A5 9 pts, CP A6 7 pts, CP B7 2 pts, CP B8 1 pts, CP B9 1 pts | 2015-2016 PSC;2017-2022 PBS | 72.6 Gy/22 fr | 96.6 Gy10 | 6.3 cm (1.0–18.5) | 19.9 mo (3.1-64.9) | 1yr 94.7% ( 1yr cumulative local recurrence 5.3%) | 1yr 79.4% 2yr 53.3% | 3 G3 GI gastroduodenal ulcer 4 RILD |
| Lin et al, 2021 | Chang Gung Memorial Hospital, Taiwan | 2014 - 2017 | retrospective | HCC patients without regional lymph node involvement or distant metastasis | 43 | 71 | PS 0 22 pts, PS 1 19 pts, PS 2 2 pts | CP A 40, CP B 3 | PSC | 25 pts 72.6 Gy/22 fr; 28pts 66Gy/10fr | 96.6 Gy10; 109.6 Gy10 | 3.1 cm (1.1–17.1) | 40 mo (9–62) | 5yr 93.0%. | 1yr 88.4%; 5yr 63.4% | 1g3 skin 7 Child-Pugh score deterioration of 1 point. |
| Bhangoo et al, 2021 | Mayo Clinic, USA | 06/2015-12/2018 | retrospective | all patients who were treated with IMPT for HCC with curative intent | 37 | 69 | PS 0 14 pts , PS 1 17 pts, PS 2 4, PS 3 2 | CP A5-6 26 pts, CP B7-9 11 pts | PBS | 15 pts 67.5 Gy /15 fr 13 pts 58.5 Gy /15 fr 15 pts 52.5 Gy /15 fr 6 pts 50 Gy /5 fr 37.5 Gy in 5 fx 1 (3%) | 97.9 Gy10, 81.3 Gy10, 70.9 Gy10, 100 Gy10, 65.6 Gy10 | 5cm (3-8) | 21 mo (17-30) | 1yr 94% | 1yr 78% | G3 pain Late 6pts increase CP by 2points |
| Iwata et al, 2021 | Nagoya Proton Therapy Center | 06/2013-12/2019 | retrospective | elderly (≥80 years old) patients. | 71 | 82 | PS 0 44 pts, PS 1 20 pts, PS 2 4 pts, PS 3 3 pts | CP A5 49 pts, CP A6 15 pts, CP B7-9 7 pts | PSC | 47 pts 66 Gy/10 Fr; 24pts 72.6 Gy/22 Fr | 109.6 Gy10; 96.6 Gy10 | 32 mm (8–111) | 33 mo (9–68) | 2yr 88% (80–97%) | 2yr 76% (66–87%) | 1G3 dermatitis |
| Dionisi et al, 2020 | Proton Therapy Unit, Trento | 01/2018-12/2019 | retrospective | unresectable disease | 14 | 67 | PS 0 11 pts, PS 1 5 pts, PS 2 2 pts | CP A5 10 pts, CP A6 2 pts, CP B7 1 pts | PBS | 60Gy (50.31–67.5) | 84 Gy10 | 4.5cm (1.2–13) | 10mo (1-19) | 100% at one year | 63% at 1 y | / |
| Kim TH et al, 2020 | National Cancer Center, Goyang, South Korea | 03/2015-09/2018 | prospective phase II | hypofractionated PBT in HCC | 45 | 63 | PS 0 45 pts | CP A 45 pts | PSC | 70Gy/10fr | 119 Gy10 | 1.6 cm (1.0–6.8) | 35.1 mo (11.2–56.3) | 3yr LPFS 95.2% | 3yr 86.4% | Child–Pugh score showed a 1-point decrease in two patients (4.4%) and no change in 43 patients (95.6%) |
| Parzen et al, 2020 | 9 institutions in the USA | 2013-2019 | prospective registry | comparative efficacy of protons versus photons in patients with HCC. | 30 HCC (63 total) | 70.5 | PS 0 13 pts, PS 1 10 pts, PS 2 5 pts, PS 3 1 pts | \ | PSC or PBS | total population: 13pts 40 GyE (32.5–50)/5fr, 46pts 58.05 GyE (45–67.5)/15fr, 4pts 71.1 GyE (60.1–75)/25fr. | 72 Gy10, 80.5 Gy10, 91.3 Gy10 | 4.3 cm (1.2–9.4) | 8.2 mo | 1yr 91.2% | 1yr 71.5% | 1G4 hyperbilirubinemia, 1G3 back pain. |
| Yoo et al, 2020 | Samsung Medical Center, Seoul, Korea | 01/2016-12/2017 | retrospective | Evaluation of the risk of biliary complications after high-dose PBT for primary HCC | 167 | 62 | PS 0 92 pts, PS 1-2 75 pts | CP A 149 pts, CP B 15 pts, CP C 3 pts | PSC 130pts, PBS 37pts; | peripheral HCCs 66 Gy in 10 fractions hcc adjacent to the porta hepatis less than 1 cm, 72.6 Gy in 22 fractions |
109.6 Gy10, 96.6 Gy10 | peripheral 48pts <=2cm; 29pts >2cm; adjacent to the porta hepatis 26pts <=2cm, 54pts >2 | 14 months (range, 1–29 months | 2ys infieldLC 86.5% | 2yr OS 86.6% | 2G 3 gastroduodenal ulcer 10 RILD 2 Non classic RILD |
| Kim TH et al, 2019 | Center for Proton Therapy, Goyang, Korea | 2012-2017 | retrospective | PVTT | 243 | 61 | PS 0 237 pts, PS 1 6 pts | CP A 228 pts, CP B7 15 pts | NA | A=40pts PTV1 50 GyE/10 fr PTV2 30 GyE/10 fr; B=60pts PTV1 60 GyE /10 fr PTV2 30 GyE/10 fr; C=143pts PTV1=PTV2 66 GyE/10 fr |
32.5 Gy10 /109.6 Gy10 | all 2.2cm (1.0–17); A 6.0 cm (1.3–17), B 3.6 cm (1.0–12), C 1.5 (1.0–12.7cm ) |
31.5 mo (2.1–68.2) | 3yr LRFS 88.6%; 5yr LRFS 87.5%; 5yr LFRS a 54.60% b 94.70% c 92.40% | 3yr 61.8%, 5yr 48.1%. 5yr: a16.70%, b39.20%, c67.90% | Child–Pugh score 19 1-point decrease, 10 1-point increase, gastric or duodenal ulcers within the PBT field 1G1 3G2 1G3 GI in regimen A. |
| Chadha et al, 2019 | MD Anderson Cancer Center | 2007-2016 | retrospective | HCC pts treated with PT | 46 | 72 | PS 0 (20%), PS 1 (25%), PS 2 (1%) | A 5 (26%) A6 (12%) B7 (6%) B8 (2%) | PSC | Median 67.5 GyE (24.0-91.0)/15 fr | 81.6 Gy10, 67 Gy10, 73,2 Gy10 | 6 cm (1.5-21.0) | 14.5 mo (0.4-59.8) | 1yr 95%, 2yr 81% | 1yr 73%, 2yr 62% | 1 G3 diarrhea; 1 G3 erithema;, 4 G3 ascites 2G3 hipeblirubinema; 1G3 Upper gastrointestinal bleeding |
| Shibata et al, 2018 | Proton Therapy Center, Fukui Prefectural Hospital, Japan | 2011-2015 | retrospective | effectiveness and toxicity of PT for hepatocellular carcinomas (HCC) >5 cm | 29 | 71 | PS 0: 21, PS 1: 7, PS 2: 1 | A: 24; B:5 | PBS | 4 pts 66Gy/10fr; 13 pts 76Gy/20fr; 1 pts 80.5Gy/23fr; 1 pts 80Gy/25fr; 1 pts 67.5Gy/25fr; 5 pts 70.4Gy/32fr; 4 pts 76 Gy/38fr | 91,3 Gy 87,4 Gy 90,6 Gy 88,5 Gy 71,4 Gy 71,6 Gy 76 Gy | 6.9 Cm (50–139) | 27 mo ( 2–72) | 2yr & 4yr 95% | 2yr 61%; 4yr 39% | ctcae 4.03 .. acute hyperbilirubinemia 1G3; Other patients had skin reactions Grade 2… late 6: pleural effusion 2G3, ascites 1G3, rib fracture 1G2, radiaton pneumonitis 1G2, erosions of ascending colon 1G2. |
| Mizuhata et al, 2018 | Proton Therapy Center, Fukui Prefectural Hospital, Japan | 03/2011-12/2015 | retrospective | efficacy and toxicity of respiratory-gated PBT without fiducial markers for HCC located within 2 cm of the gastrointestinal tract. | 40 | 72 | PS 0,1: 38 \ PS 2: 2 | A: 28; B: 12 | PBS | 1 pts 80.0 CGE/25fr 5 pts 76.0 CGE/38fr 17 pts 76.0 CGE/20fr 3 pts 74.8 CGE/34fr 8 pts 70.4 CGE/32fr 3 pts 70.0 CGE/35fr 1 pts 67.5 CGE/25fr 1 pts 66.0 CGE/30fr 1 pts 52.8 CGE/24fr | 88 Gy 76 Gy 87,4 Gy 76,1 Gy 71,6 Gy 76 Gy 71,4 Gy 67,1 Gy 53,7 Gy | 3.6 cm (1.1–12.4) | 19.9 mo (1.2–72.3) | 2yr 94% | 1yr 86%; 2yr 76% | 1 G3 gastric ulcer, 1 G3 ascites retention |
| Lee et al, 2018 | Chang Gung Memorial Hospital, Taiwan | 2015-2016 | retrospective | HCC patients with small normal liver volume (NLV) | 22 | 61,5 | PS 0:7; PS 1: 13 | PBS | median 72.6 GyE/22 fr | median 80,7 Gy10 | 5.3cm (1.2-15.0) | 15.7 mo (4.0±24.9) | 1yr 95.5% | 1yr 91.8% | 1G3 esophagitis 1G3 colitis; Child±Pugh score deterioration of one point 3 pts; 1G3 liver enzyme elevations |
|
| Kim et al, 2018 | National Cancer Center, Goyang, Korea | 2013-2015 | retrospective | inoperable or recurrent HCC | 71 | 63 | PS 0: 100% | A: 68; B: 3 | PSC | 66 GyE/10 fr | 91,3 Gy10 | 1.5cm (1.0–8.5) | 31.3 mo (4.2–47) | 3yr LPFS 89.9% (81.8–98%) | 3yr 74.4% (63.1–85.7%) | Child–Pugh score 3pts 1-point increase. |
| Kimura et al, 2017 | Radiation Oncology, Southern Tohoku Proton Beam Therapy Center | 2008-2015 | retrospective | HCC > 5 cm | 24 | 73 | PS 0:16; PS 1: 8 | A: 100% | NA | 72.6 GyE (60.8-85.8 GyE) 2.4 (2.2-6.6)Gy/fr | 75 Gy10 | 5-18 CM | 17.5 mo (3-64) | 2yr 87% | 2yr 52.4% | 2G3 radiation dermatitis; |
| Hong et al, 2016 | Multinstitutional | 2009-2015 | phase II prospective | HCC and ICC | 44 HCC | 70,5 | PS 0:14, PS 1: 26, PS 2: 3 | A:32, B:9, No cirrhosis: 3 | PSC | 58.0 Gy (40.5-67.5) in 15 FR | 42.8 Gy10/81.5Gy10 | 5 cm (1.9-12.0) | All pts 19.5 months (0.6 - 55.9 months) | 2yr 94.8% | 1yr 76.5%, 2yr 63.2% | .1 G3 thrombocytopenia. |
| Fukuda et al, 2016 | Proton Medical Research Center, Tsukuba, Japan | 2002-2009 | retrospective | previously untreated HCC | 129 | 72 | PS 0:70, PS 1:50, PS 2:9 | A:101 B:28 | PBS | 54 pts 66GyE/10fx; 45 72.6GyE/22fx; 30 77GyE/35fx | 91,3 Gy; 80,5 Gy; 78,3 Gy | 3.9 cm(1–13.5) | 55 mo (43-67) | 5yr 94% (82-100%) | 5-year OS rates were 69% (95% CI, 49–89%) for stage 0/A patients, 66% (95% CI, 48–84%) for stage B patients, and 25% (95% CI, 11–40%) for stage C patients | NONE |
| Bush et al, 2016 | Loma Linda University Medical Center, Usa | NA | randomizedclinical trial: PT vs TACE | interim analysis report | 33 | 61,4 | N.A. | N.A. | PSC | 70.2 CGE/15 fr | 86 Gy10 | 3.2 cm(1.8-6.5) | 28mo | 2yr LC 88% | 2yr OS 59% | 2 pts requiring hospitalization for liver failure |
| Kim et al, 2015 | National Cancer Center, Goyang, Korea | 2007-2010 | phase I | Dose finding | 27 | DL_1:70; DL_2:66; DL_3:63 | PS 0:21; PS 1: 6 | A: 24; B: 3 | PSC | 8 DL 1 60 GyE/20 fr; 7 DL 2 66 GyE/22 fr; 12 DL 3 72 GyE/24 fr |
DL 1 65 Gy10
DL 2 71.5 Gy10 DL 3 80.2 Gy10 |
DL 1 3.2cm(2-7); DL 2 2.3cm(1.5-5); DL 3 2.5cm(1.3-6.2) | 31 mo (5.2-63.4) | 3yr LPFS 79.9% 5yr LPFS 63.9% |
3yr 56.4% 5yr 42.3% | 1 patient 1-point increase in CP score. |
| Lee et al, 2014 | National Cancer Center, Goyang, Korea | 2008-2011 | retrospective | HCC with PVTT | 27 | 55 | PS 0:18; PS 1: 9 | A: 18; B: 9 | NA | median 55GyE (50–66 GyE)/20–22 fr | Max 71.5 Gy10 | 7cm (3–16) | 13.2 mo (2.4–51.7) | 1yr LPFS 70.7%; 2yr LPFS 61.9% |
1yr 55.6%; 2yr 33.3% | 4 pts 1-point increase in CP score. |
| Sanford et al, 2019 | Massachusetts General Hospital, USA | 2008/2017 | retrospective | unresectable HCC | 49 | 65 | PS 0 23 pts; PS 1 24 pts, PS 2/3 2 pts | CP A 46 38 pts, CP B/C 8 pts | PSC | Various treatmetn schedules, the most adopted being 58GyE/15fr; | 67 Gy10 | NA | 14mo (all pts) | 2yr 93% | 2 yr 59.1% | 4 nonclassic RILD |
| Hojo et al, 2019 | National Cancer Center Hospital East, Chiba, Japan | 2008-2015 | retrospective | anatomic subsegmental PT irradiation | 110 | 74 | PS 0 72 pts; PS 1-2 38 pts | CP A 95 pts, CP B 15 pts | PSC | 76 Gy ()/20 fr | 87.4 Gy10 | 74pts < 5 cm 36pts > 5 cm | 36.5 mo (1-99.6 mo) | 3yr 91.7% | 3yr 74.2% | 1 G3 radiation pneumonitis 1G3 liver dysfunction and 1 G3 bile duct stenosis. 1G5 radiation pneumonitis on day 188 after the start of PT |
| Tamura et al, 2019 | Shizuoka Cancer Center Hospital, Japan | 2003-2017 | retrospective | single nodular HCC≤100 mm without vessel invasion | 31 | 72 | PS 0 20 pts; PS 1 10 pts, PS 2 1 pts | CP A 29 pts, CP B 2 pts | NA | 8pts 66 GyE/10 Fr 22 pts 72.6–76 GyE/20–22 Fr 1pts 74–76 GyE/37–38 Fr | 109.6 Gy10, 102.3 Gy10, 91.2 Gy10 | 3.5.Cm (1–9) | 56.3 mo (22.2–82.3) | 19.4% Local recurrence | 3 yr 69.2%, 5yr 51.1% | 1 G3 gastric ulcer |
| Sekino et al, 2019 | Proton Medical Research Center, Tsukuba, Japan | 2005-2014 | retrospective | HCC pts with IVCTT | 21 | 73 | PS 0 12 pts; PS 1-3 9 pts | CP A 12 pts, CP B 9 pts | PBS | 50–74 (median 72.6) | 109.6 Gy10 median | 8 cm (3.9–20) | 21 mo (4–120) | 100% | 1yr OS 82%, 2yr OS 64%, 3 yr OS 36% | none |
| Yoo et al, 2020 | Samsung Medical Center, Seoul, Korea | 2016-2017 | retrospective | compare the oncologic outcomes and toxicities between PS and PBS | 172 | 62 | PS 0 90 pts, PS 1-2 79 pts | CP A 154 pts, CP B 18 pts | 133 PSC, 39 PBS | 33 pts 50 Gy in 10 fractions 116 pts 60–66 Gy in 10 fractions 23 pts other schedules |
75 Gy10, 109.6 Gy10, 132 Gy10 | PS 3.1 (1–16); PBS 6.7 (1–19) | 14 months (range, 1–31 months). | 2-year 85.5%, | 2-year OS 86.4% | RILD PS 2 pts PBS 1 patient 2 GI G3 (PS) |
| Iwata et al, 2021 | Nagoya Proton Therapy Center, Japan | 2013-2016 | phase II | Operable or Ablation-Treatable HCC | 45 | 68 | PS 0 43 pts, PS 1 3 pts | CP A5 32, CP A6 9 pts, CP B7 4 pts | PSC | 8 pts 72.6 Gy in 22 fr, 37 pts 66 Gy in 10 fr |
96.6 Gy10, 109.6 Gy10 | 2.5 cm (1-10) | 53 months (range, 9.5-75 months) | , 2yr LC 95%, 2yr PFS 62% | OS 5yr 70% | NO RILD, 1 G3 AST/ALT increase |
| Iizumi et al, 2021 | Proton Medical Research Center, Tsukuba, Japan | 2002-2014 | retrospective | patients who received PBT for HCC in the caudate lobe | 30 | 67 | PS 0 12 pts, PS 1 17 pts, PS 2 1 | CP A5 17 pts, CP A6 7 pts, CP B7 3 pts, CP B8 1 pts, CP C 1 pts, 1 pts N.A. | PSC | 72.6 Gy in 22 fr (70%), 55 Gy in 10 fr (3.3%), 60 in 15 fr (3.3%), 74 in 37 fr (16.7%), 77 in 35 fr (6.7%) |
96.6 Gy10, 85.2 Gy10, 84 Gy10, 88.8 Gy10, 93.9 Gy10 | 2.3 Cm (1-9) | 37.5 months (3–152 months) | 1yr LC 100%, 3yr LC 85.9%, 5yr LC 85.9%, 1yr PFS 65%, 3yr PFS 27.5%, 5yr PFS 22% |
Os 1yr 86.6%, OS 3yr 62.8%, OS 5yr 46.1% | none |
| Hsieh et al, 2019 | Chang Gung Memorial Hospital, Taiwan and MD Anderson Cancer Center, USA | 2007-2017 | retrospective | HCC who underwent definitive PT. | 136 | 68 | PS 0 68 pts, PS 1 64 pts, PS 2 4 pts | CP A5 92 pts, CP A6 25 pts, CP B7 13 pts, CP B8 6 pts | NA | 72.6 Gy/22 fr ; 66 Gy/10 fr; 67,5 Gy/15 fr; 58 Gy/15 fr; 66 Gy/20 fr |
80.5 Gy10, 91.3 Gy10, 81.6 Gy10, 67 Gy10, 73.2 Gy10 | Median 6.8 cm in the eastern and 6.4 cm in the western pts, respectively. | 10 mo (range, 5-27 months) and 23 mo (range, 3-76 mo) for the eastern and western patients, respectively | N.A. | N.A. | 19 (14%) pts developed RILD |
| Chiba et al, 2005 | Proton Medical Research Center, University of Tsukuba. | 1985-1998 | retrospective | pts unfit for surgery | 162 | 62,5 | PS 0 61; PS 1 79; PS 2 21; | CP A 82 CP B 62 CP C 10 | PSC | 72 Gy/16 fr 64 courses 78 Gy/20 fr 11 courses 84 Gy/20 fr 10 courses 50 Gy/10 fr 10 courses Miscellanous regimens 97 courses |
87 Gy10; 90,4 Gy10; 94,5 Gy10; 62,5 Gy10 |
3 - 5 mm (108 pts) | 31,7 months (3,1 to 133,2) | 5 yr 89,6% | 5 yr : 23,5% | Elevation of transaminase level 9,7%; Thrombocytopenia 3.2%. |
| Komatsu et al, 2011 | Hyogo Ion Beam Medical Center, Tatsuno, Japan | 2001-2009 | Retrospective | All pts treated with PT for HCC | 242 | < 70 115 pts ≥ 70 127 pts |
PS 0 172; PS 1 57; PS2 10 PS 3 3 | CP A 184 CP B 55 CP C 3 | PSC | 76 Gy/20 Fr 70 pts 60 Gy/10 Fr 89 pts 66 Gy/10 Fr 53 pts miscellanous regimens 30 pts |
104.8Gy10
96 Gy10 109.5 Gy10 |
< 5 cm 196 5-10 cm 67 > 10 cm 17 |
31 mo | 90.2% at 5 yr | 38% at 5yr | 1G4 dermatitis 4G3 dermatitis 1 G3 Elevation of transaminase level 1G3 GI ulcer 1 G3 biloma |
| Kawashima et al 2005 | National Cancer Center Hospital East, Chiba, Japan | 1999-2003 | Propsective | Phase II study | 30 | 70 | PS 0-1 29 PS 21 | CP A 20 CP B 10 | PSC | 76 Gy/20 Fr | 104.8Gy10 | 4.5 cm | 31 mo | 96% at 2 yr | 66% at 2yr | 5 G3 Elevation of transaminase level 5 G3 Leukopenia 7 G3 Thrombocytopenia 1 G3 bilirubine 8 pts developed PHI |
PSC, passive scattering; PBS, pencil beam scanning; PS, performance status; CP, Child-Pugh; pts, patients. GI, gastrointestinal; PHI, proton-inducing hepatic insufficiency; mo, months; yr, years. Refer to the text for othe abbreviations.